Elevated platelet count is associated with decreased mortality from hemorrhagic stroke in hospital: a multi-center retrospective cohort study

This study aimed to investigate the relationship between platelet count (PC) and mortality in patients with hemorrhagic stroke (HS). The research reviewed data from 10,466 patients hospitalized in 208 hospitals in the United States from January 1, 2014, to December 31, 2015. Of these, 3262 HS patients were included in the primary analysis for those admitted to the intensive care unit (ICU). The average age of these patients was 67.05 years, with 52.79% being male. The median PC was (221.67 ± 73.78) × 109/L. Multivariate logistic regression analysis revealed that PC was a protective factor for mortality in HS patients (OR = 0.98, 95% CI 0.97–1.00, P < 0.05). Additionally, a non-linear association between PC and mortality in HS patients was found using a generalized additive model (GAM) and smooth curve fitting (penalty spline method). For the first time, a recursive algorithm identified the inflection point of platelet count as 194 × 109/L. On the left side of the inflection point, for every increase of 10 units in platelet count, the mortality rate of HS patients decreases by 10%. The study demonstrates a non-linear relationship between PC and the risk of mortality in HS patients. A platelet counts higher than the inflection point (194 × 109/L) may be a significant intervention to reduce mortality in HS patients.

www.nature.com/scientificreports/ The transfusing of a minimum platelet threshold of 50 × 10 9 /L for trauma, preprocedural and major bleeding is widely upheld [15][16][17] , but without good-quality evidence.Currently, the best threshold for patients who received platelet transfusions remains unclear, and in some cases, this depends on the doctor's clinical experience and the patient's clinical diagnosis 18 .This retrospective study aimed to explore the association between PC and mortality in hospitalized stroke patients, and to identify the optimal PC threshold for minimizing mortality in HS patients.

Baseline characteristics
Table 1 summarizes the demographic and clinical characteristics of the 3,262 hemorrhagic stroke patients included in the study, with a mean age of 67.05 ± 14.89 years.Among them, 52.79% were male, and 47.21% were female, predominantly Caucasian (74.92%).Throughout the study, 13.67% experienced in-hospital mortality.The median platelet count was 221.67 ± 73.78 × 10^9/L, mostly within the normal range.

Relationship between PC and mortality of HS patients in different models
In the unadjusted model (crude model), a 10-unit increase in PC was associated with a 20% decrease in the risk of HS patients' death in the hospital (HR = 0.98, 95% CI: 0.97-0.99P = 0.0028).In the minimally adjusted model (model I), each additional 10-unit increase in PC decreased the risk of death of hospitalized HS patients by 20% (OR = 0.98, 95% CI 0.97-1.00,P = 0.00159).In the fully adjusted model (model II), each additional 10-unit increase in PC was accompanied by a 20% decrease in death risk in HS patients in the hospital (OR = 0.98, 95% CI 0.97-1.00,P = 0.00259).The distribution of the confidence intervals indicated that the relationship between PC and death risk in HS patients was reliable and stable.However, when we assessed the subgroups based on PC, the results showed that the hospital mortality of HS patients was lower in T2 and T3 compared with T1 (Table 3).

Non-linear relationship of PC with in-hospital mortality of HS patients
Smoothing splines were generated utilizing a generalized additive model and adjusted for age, sex, ethnicity, AF, ACS, diabetes and sepsis.The results showed that the link between PC and mortality of HS patients was non-linear (Fig. 1).In addition, we found that the inflection point of PC was 194 × 10 9 /L using a recursive algorithm.Then, we calculated the OR and CI on the left and right of the inflection point.The results showed that the HR was 0.99 on the left side of the inflection point (95% CI: 0.99-1.00)(P = 0.0026).In addition, when PC was < 194 × 10 9 /L, a 10-unit (× 10 9 /L) increase in PC was associated with a 10% decrease in HS-related morality.
The HR was 1.00 on the right side of the inflection point (95% CI:1.00-1.00)(P = 0.8417), but the difference was not statistically significant (Table 4).

Discussion
This retrospective cohort study examined the association between PC and the mortality of HS patients and demonstrated that PC was an independent risk factor for the mortality of hospitalized HS patients.Moreover, the present study observed a non-linear relationship between PC and the risk of in-hospital death in HS patients.In addition, we first demonstrated that the inflection point of PC was 194 × 10 9 /L, and notably, when PC was < 194 × 10 9 /L, the magnitude of PC increase correlated significantly with the decrease in all-cause mortality in HS patients.HS occurs as a result of cerebral hemorrhage due to the rupture of blood vessels, which can lead to severe morbidity and high mortality.Progression of HS has been associated with worse patient prognoses and severity of HS.The risk factors for mortality in hemorrhagic stroke primarily involve hypertension, impaired  Table4.The result of the two-piecewise linear regression model.www.nature.com/scientificreports/erythrocyte deformability, and endothelial dysfunction.Each of these factors may contribute to an increased risk of bleeding 19,20 .Currently, some studies reported PC as a good predictor of mortality in HS.Platelet dysfunction, for instance, based on vascular endothelial growth factors released from activated platelets, was reported to be a crucial factor inducing HS 21,22 .Therefore, it is essential to actively search for the association between platelet and the prognosis of HS patients to identify ways to improve their treatment outcomes.A retrospective study involving 445 cases found that an increased platelet count is a risk factor for ischemic stroke, while a decreased PC is a risk factor for hemorrhagic stroke 12 .Another prospective study involving 738 patients with acute ischemic/hemorrhagic stroke, including 44 with ischemic stroke and 29 with hemorrhagic stroke, found a negative correlation between platelet count and hemorrhagic stroke.However, this study was a single-center study with a small sample size, possibly leading to selection bias 13 .A retrospective study using prospectively collected data found that the platelet-to-lymphocyte ratio (PLR) was significantly associated with poor prognosis and mortality risk in patients before and 24 h after rtPA thrombolytic therapy 23 .However, there are currently no studies on the relationship between platelet count and the prognosis of hemorrhagic stroke.Therefore, this study explored the correlation between platelet count and in-hospital mortality in hemorrhagic stroke.
In this study, a cohort of 3262 HS patients was examined.Upon admission, the platelet levels of most patients fell within the normal range, with only a few presenting thrombocytopenia, a common marker in critically ill individuals.Notably, our analysis revealed a significantly higher mortality rate among HS patients in the low PC group compared to the high PC group.Furthermore, a negative correlation was observed between increasing PC levels and a decrease in in-hospital mortality among HS patients.Employing GAM and smooth curve fitting, our investigation highlighted a non-linear relationship between PC levels and the risk of in-hospital mortality in HS patients.After adjusting for confounding factors, the inflection point of PC was determined to be 194 × 10 9 /L.Below this threshold, a 10-unit increase in PC correlated with a noteworthy 10% reduction in in-hospital mortality for HS patients.Intriguingly, when PC exceeded 194 × 10 9 /L, the risk of hospital death in HS did not exhibit a significant decrease with further increases in PC.These findings emphasize that the elevation of PC, if it remains below 194 × 10 9 /L, serves as an independent protective factor for patients with HS.The outcomes of our study address a longstanding issue and furnish a solid clinical foundation for the treatment of hemorrhagic strokes.
Compared to other studies, our research is the first to explore the association between platelet count and the prognosis of patients with hemorrhagic stroke.In addition, the robustness of the data is related to the relatively large sample size, based on which we observed a non-linear relationship between PC and the risk of in-hospital death in HS patients.Further, we also found that the inflection point of PC was 194 × 10 9 /L, which played a crucial role in modulating platelet to improve the prognosis of HS in clinical practice.
The primary reasons for thrombocytopenia in HS patients include increased platelet destruction, reduced platelet production, platelet dilution, or aggregation.For instance, patients with immune diseases like systemic lupus erythematosus are most prone to thrombocytopenia 24 .Moreover, patients without systemic diseases might also have thrombocytopenia, potentially induced by pharmacological agents like antiplatelet drugs and cephalosporins 25,26 .Additionally, HS complicated by severe sepsis and hypersplenism can directly diminish platelet count.Furthermore, other severe illnesses might impair the bone marrow's hematopoietic function, leading to diminished platelet levels [27][28][29] .Based on this study's findings, appropriate etiological treatment or platelet transfusion may be beneficial for the prognosis of HS patients.
The results of this study have certain clinical implications.Firstly, the study highlighted that in patients with HS, a low PC is significantly associated with higher in-hospital mortality.This emphasizes the importance of monitoring patients' platelet count in the early assessment of hemorrhagic stroke.Secondly, by using GAM and smoothing curve fitting, the study identified the inflection point of PC levels as 194 × 10 9 /L.This finding suggests that for each increase of 10 count units below this threshold, there is a significant reduction in in-hospital mortality for HS patients.Therefore, the PC level becomes a clinical indicator for predicting the in-hospital survival rate of patients.The results underline that when PC levels rise but remain below 194 × 10 9 /L, they act as an independent protective factor, significantly reducing the risk of in-hospital mortality in HS patients.This provides a guideline for clinicians, suggesting that maintaining or increasing platelet levels within this range may be beneficial for patients' prognosis.
However, there were also some potential limitations associated with this study.First, this was a retrospective analysis of a prospective registry study.We did not have data on multiple PC at different time intervals; hence, we could not explore the association between the change in PC with HS patients' prognoses.Further, we could not determine long-term outcomes because only short-term follow-up data were available in the database.Thus, further studies, such as randomized clinical trials, on the relationship between PC and stroke are needed to confirm our findings.

Conclusion
For the first time, we report a non-linear relationship between PC and mortality risk in hospitalized HS patients.An elevated PC above the inflection point (194 × 10 9 /L) could lead to a decreased mortality of HS patients.when PC was > 194 × 10 9 /L, the risk of in-hospital death in HS did not significantly decrease with an increase in the PC.

Ethics statement
This study analyzed a publicly available, anonymized database with the Institutional Review Board of the Massachusetts Institute of Technology (Cambridge, Massachusetts, USA) approval, which permits unrestricted use, distribution, and reproduction in any medium.One author (Zhenhua Huang) obtained access rights and was responsible for data extraction (certification number:49995491).The data was the current secondary analysis, https://doi.org/10.1038/s41598-024-53956-7

Figure 1 .
Figure 1.The nonlinear relationship of PC with in-hospital mortality of HS patients.The smoothing splines were generated utilizing generalized additive model and adjusted for age, sex, ethnicity, AF, ACS, diabetes and sepsis.The red line indicates the risk of mortality and the blue dot line indicates 95% confidence intervals.

Factors influencing the risk of hospitalized HS patients' death by univariate analysis As
shown in Table2, univariate analyses showed that PC was associated with the hospital mortality of HS patients (P < 0.05).Similar results were found for age, levels of HGB, BUN, ACS rate, CHF rate, diabetes rate and sepsis rates (all P < 0.05).However, hospitalized HS patients' death was not associated with sex, ethnicity, BMI, cancer rate, hypertension rate, GIB rate, or drugs used (all P > 0.05).

Table 3 .
Relationship between PC and hospitalized HS patients' death in different models.Non-adjusted model: no covariates were adjusted for.Adjusted model I: we only adjusted for age, sex and ethnicity.Adjusted model II: we adjusted for age, sex, ethnicity, AF, ACS, diabetes and sepsis.